Amorphous solid dispersions

ABSTRACT

The disclosure provides new, stable, pharmaceutically acceptable amorphous solid dispersions of 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one, together with methods of making and using them, and pharmaceutical compositions comprising them.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part, filed under 35 U.S.C. § 111,of international application PCT/US2017/054962, filed on Oct. 3, 2017,which claims priority to and the benefit of U.S. Provisional ApplicationSer. No. 62/407,285, filed on Oct. 12, 2016, the content of each ofwhich are hereby incorporated by reference in their entireties.

FIELD

This disclosure relates to certain novel amorphous solid dispersionformulations of a substituted heterocycle fused gamma-carboline, themanufacture of such dispersions, pharmaceutical compositions comprisingsuch dispersions, and uses thereof, e.g., in the treatment of diseasesor abnormal conditions involving or mediated by the 5-HT_(2A) receptor,serotonin transporter (SERT), and/or dopamine D₁/D₂ receptor signalingpathways.

BACKGROUND

1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(sometimes referred to as4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone,or Lumateperone or as ITI-007), has the following structure:

ITI-007 is a potent 5-HT_(2A) receptor ligand (Ki=0.5 nM) with strongaffinity for dopamine (DA) D2 receptors (Ki=32 nM) and the serotonintransporter (SERT) (Ki=62 nM), but negligible binding to receptorsassociated with cognitive and metabolic side effects of antipsychoticdrugs (e.g., H1 histaminergic, 5-HT_(2c), and muscarinic receptors).ITI-007 is currently in clinical trials, i.e., for the treatment ofschizophrenia. While ITI-007 is a promising drug, its production andformulation present distinct challenges. In free base form, ITI-007 isan oily, sticky solid, with poor solubility in water. Making salts ofthe compound has proven to be unusually difficult. A hydrochloride saltform of ITI-007 was disclosed in U.S. Pat. No. 7,183,282, but this saltwas hygroscopic and shows poor stability. A toluenesulfonic acidaddition salt (tosylate) of ITI-007 was finally identified and describedin WO 2009/114181. Both of these publications are incorporated byreference in their entirety.

Nevertheless, there remains a need for alternative stable,pharmaceutically acceptable solid forms of ITI-007 which can be readilyincorporated into galenic formulations.

It has been disclosed that for a number of drugs, amorphous formsexhibit different dissolution characteristics, and in some casesdifferent bioavailability patterns, compared to crystalline forms of thesame drug. For some therapeutic indications, one bioavailability patternmay be favored over another. For example, an amorphous form ofCefuroxime axetil exhibits higher bioavailability than the crystallineform. Thus, amorphous solid dispersions are a promising alternative totraditional crystalline active pharmaceutical ingredients.

Pure amorphous drug forms tend to be unstable. As amorphous forms arethermodynamically unstable relative to the corresponding crystal forms,it is well known that amorphous forms would revert back to the stablecrystalline form. This usually occurs during storage under varioushumidity and temperature conditions. Therefore, in order to utilize theamorphous form of a drug, it is necessary to stabilize it to inhibitcrystallization of the drug active during the period of product storage.

Discovering suitable excipients that will stabilize the amorphous formof a pharmaceutical drug is a challenge, as some excipients willchemically react with the drug or promote its decomposition, while otherexcipients will form uniform solid dispersions that are not physicallystable, not chemically stable or both.

SUMMARY

Given the difficulties involved in making salts of ITI-007, it wasdecided to explore whether the compound could be formulated as aphysically and chemically stable amorphous solid dispersion. Anextensive screen of excipients was undertaken, using variouscombinations of agents at different ratios and using differentproduction methods. Dispersions were evaluated based on physicalappearance and texture, X-ray powder diffraction (XRPD), modulateddifferential scanning calorimetry (mDSC), thermogravimetric analysis(TGA), and high-performance liquid chromatography (HPLC). Sixteenpotential excipients were screened under a total of forty-fourconditions, and three pharmaceutically acceptable amorphous soliddispersions were discovered.

The present disclosure therefore provides amorphous solid dispersions ofITI-007 in free base form or in tosylate salt form, in admixture withone or more excipients, such as stabilizing excipients.

In one aspect, the present disclosure provides three particularly stableamorphous solid dispersions of ITI-007 free base comprising (1) ITI-007free base at a 5:95 to 50:50 weight ratio to cellulose acetateexcipient; (2) ITI-007 free base at a 25:75 to 75:25 weight ratio tocellulose acetate phthalate excipient; and (3) ITI-007 free base at a25:75 to 75:25 weight ratio to hydroxypropyl methyl cellulose phthalateexcipient. The present disclosure further provides several amorphoussolid dispersions of ITI-007 tosylate, optionally further comprising anantioxidant and/or a surfactant.

The disclosure thus provides novel amorphous solid dispersion forms ofITI-007 free base and tosylate salt, which dispersions are especiallyadvantageous for use in the preparation of galenic formulations,together with methods of making and using the same.

Further areas of applicability of the present invention will becomeapparent from the detailed description provided hereinafter. It shouldbe understood that the detailed description and specific examples, whileindicating preferred embodiments of the invention, are intended forpurposes of illustration only and are not intended to limit the scope ofthe invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will become more fully understood from thedetailed description and the accompanying drawings, wherein:

FIG. 1 depicts an overlay of X-ray powder diffraction patterns fordispersions of ITI-007 free base with cellulose acetate.

FIG. 2 depicts an overlay of X-ray powder diffraction patterns fordispersions of ITI-007 free base with cellulose acetate phthalate.

FIG. 3 depicts an overlay of X-ray powder diffraction patterns fordispersions of ITI-007 free base with hydroxypropyl methyl cellulosephthalate (grade 55) (HPMC-P).

For each of FIGS. 1, 2 and 3 , the top pattern is the 25:75 ITI-007 freebase/excipient dispersion as-generated; the second pattern is the 25:75dispersion post-stress; the third pattern is the 50:50 ITI-007 freebase/excipient dispersion as-generated; the bottom pattern is the 50:50dispersion post-stress.

FIG. 4 depicts mDSC and TGA thermograms for a 25:75 dispersion ofITI-007 free base with cellulose acetate.

FIG. 5 depicts mDSC and TGA thermograms for a 50:50 dispersion ofITI-007 free base with cellulose acetate phthalate.

FIG. 6 depicts mDSC and TGA thermograms for a 50:50 dispersion ofITI-007 free base with HPMC-P.

DETAILED DESCRIPTION

The following description of the preferred embodiment(s) is merelyexemplary in nature and is in no way intended to limit the invention,its application, or uses.

As used throughout, ranges are used as shorthand for describing each andevery value that is within the range. Any value within the range can beselected as the terminus of the range. In addition, all references citedherein are hereby incorporated by referenced in their entireties. In theevent of a conflict in a definition in the present disclosure and thatof a cited reference, the present disclosure controls.

Unless otherwise specified, all percentages and amounts expressed hereinand elsewhere in the specification should be understood to refer topercentages by weight. The amounts given are based on the active weightof the material.

The present disclosure provides amorphous solid dispersions of1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(ITI-007), either in free base form or in tosylate salt form, inadmixture with one or more excipients, such as stabilizing excipients

In a first embodiment, the present disclosure provides1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(ITI-007) free base in the form of an amorphous solid dispersioncomprising cellulose acetate excipient in a ratio of 5:95 to 50:50ITI-007 free base to cellulose acetate (Dispersion 1). The presentdisclosure further provides the following Compositions:

-   -   1.1. Dispersion 1, wherein the dispersion comprises ITI-007 free        base and cellulose acetate in a weight ratio of 5:95 up to        50:50, but excluding the ratio 50:50.    -   1.2. Dispersion 1 or 1.1, wherein the dispersion comprises        ITI-007 free base and cellulose acetate in a weight ratio of        5:95 to 49:51, e.g., 5:95 to 45:55, or 10:90 to 40:60, or 15:85        to 35:65, or 20:80 to 30:70, or 22:78 to 28:82, or 23:77 to        27:83, or 24:76 to 26:74, or about 25:75.    -   1.3. Any foregoing dispersion, wherein the dispersion is x-ray        amorphous, e.g., as shown by XRPD analysis.    -   1.4. Any foregoing dispersion, wherein the X-ray diffraction        pattern is free of peaks characteristic of the excipient.    -   1.5. Any foregoing dispersion, wherein the dispersion shows a        single glass transition temperature (T_(g)) above 75° C., e.g.,        at a temperature above 100° C., or at a temperature above 150°        C., e.g., as shown by mDSC analysis.    -   1.6. Dispersion 1.5, wherein the dispersion shows a single glass        transition temperature above 160° C., or between 165° C. and        170° C., or at about 167° C.    -   1.7. Any foregoing dispersion, wherein the dispersion shows a        change in heat capacity (ΔCp) of 0.1 to 0.5 J/g-° C., e.g., from        0.2 to 0.3 J/g-° C., or about 0.2 J/g-° C., e.g., as shown by        mDSC.    -   1.8. Any foregoing dispersion, wherein the dispersion shows less        than 10% weight loss up to a temperature of 100° C., e.g., as        shown by TGA analysis.    -   1.9. Dispersion 1.8, wherein the dispersion shows less than 8%        weight loss up to a temperature of 100° C., e.g., less than 7%        weight loss, or less than 6% weight loss, or less than 5% weight        loss, or less than 4% weight loss, or less than 3% weight loss,        up to a temperature of 100° C.    -   1.10. Any foregoing dispersion, wherein the dispersion shows no        changes in appearance or texture after 7 days at 75% relative        humidity at 40° C.    -   1.11. Any foregoing dispersion, wherein the dispersion shows        greater than 90% chemical stability of ITI-007 after 7 days at        75% relative humidity at 40° C., e.g., as judged by HPLC.    -   1.12. Dispersion 1.11, wherein the dispersion shows greater than        95%, or greater than 96%, or greater than 97% or greater than        98%, or greater than 99% chemical stability of ITI-007 after 7        days at 75% relative humidity at 40° C.    -   1.13. Any foregoing dispersion, wherein the dispersion is        manufactured by a method comprising dissolving ITI-007 free base        and the selected excipient in a suitable solvent or mixture of        solvents and removing the solvent, e.g., by lyophilizing the        solution, to obtain the amorphous solid dispersion.    -   1.14. Dispersion 1.13, wherein the solvent or mixture of        solvents is selected from dioxane, methanol, ethanol,        tetrahydrofuran, acetone, and mixtures thereof.    -   1.15. Dispersion 1.13, wherein the solvent or mixture of        solvents is selected from dioxane, methanol or a        dioxane/methanol mixture, e.g., a 90:10 to 98:2 ratio of dioxane        to methanol, or a 92:8 to 95:5 ratio, or about a 93:7 ratio of        dioxane to methanol.    -   1.16. Any foregoing dispersion, wherein the dispersion exhibits        any combination of characteristics as described in 1.1-1.15.

In a second embodiment, the present disclosure provides ITI-007 freebase in the form of an amorphous solid dispersion comprising celluloseacetate phthalate excipient in a ratio of 25:75 to 75:25 ITI-007 freebase to cellulose acetate phthalate (Dispersion 2). The presentdisclosure further provides the following Compositions:

-   -   2.1. Dispersion 2, wherein the dispersion comprises ITI-007 free        base and cellulose acetate phthalate in a weight ratio of from        25:75 up to 75:25, but excluding the ratios 25:75 and 75:25.    -   2.2. Dispersion 2 or 2.1, wherein the dispersion comprises        ITI-007 free base and cellulose acetate phthalate in a weight        ratio of 26:74 to 74:26, e.g., 30:70 to 70:30, or 35:65 to        65:35, or 40:60 to 60:40, or 42:58 to 58:42, or 44:56 to 56:44,        or 45:55 to 55:45, or 47:53 to 53:47, or 48:52 to 52:48, or        49:51 to 51:49, or about 50:50.    -   2.3. Any foregoing dispersion, wherein the dispersion is x-ray        amorphous, e.g., as shown by XRPD analysis.    -   2.4. Any foregoing dispersion, wherein the X-ray diffraction        pattern is free of peaks characteristic of the excipient.    -   2.5. Any foregoing dispersion, wherein the dispersion shows a        single glass transition temperature (T_(g)) above 75° C., e.g.,        at a temperature above 85° C., or at a temperature above 95° C.,        e.g., as shown by mDSC analysis.    -   2.6. Dispersion 2.5, wherein the dispersion shows a single glass        transition temperature above 100° C., or between 105° C. and        115° C., or at about 107° C.    -   2.7. Any foregoing dispersion, wherein the dispersion shows a        change in heat capacity (ΔCp) of 0.1 to 0.6 J/g-° C., e.g., from        0.2 to 0.5 J/g-° C., or about 0.4 J/g-° C., e.g., as shown by        mDSC.    -   2.8. Any foregoing dispersion, wherein the dispersion shows less        than 10% weight loss up to a temperature of 100° C., e.g., as        shown by TGA analysis.    -   2.9. Dispersion 2.8, wherein the dispersion shows less than 8%        weight loss up to a temperature of 100° C., e.g., less than 7%        weight loss, or less than 6% weight loss, or less than 5% weight        loss, or less than 4% weight loss, or less than 3% weight loss,        up to a temperature of 100° C.    -   2.10. Any foregoing dispersion, wherein the dispersion shows no        changes in appearance or texture after 7 days at 75% relative        humidity at 40° C.    -   2.11. Any foregoing dispersion, wherein the dispersion shows        greater than 90% chemical stability of ITI-007 after 7 days at        75% relative humidity at 40° C., e.g., as judged by HPLC.    -   2.12. Dispersion 2.11, wherein the dispersion shows greater than        95%, or greater than 96%, or greater than 97% or greater than        98%, or greater than 99% chemical stability of ITI-007 after 7        days at 75% relative humidity at 40° C.    -   2.13. Any foregoing dispersion, wherein the dispersion is        manufactured by a method comprising dissolving ITI-007 free base        and the selected excipient in a suitable solvent or mixture of        solvents and removing the solvent, e.g., by lyophilizing the        solution, to obtain the amorphous solid dispersion.    -   2.14. Dispersion 2.13, wherein the solvent or mixture of        solvents is selected from dioxane, methanol, ethanol,        tetrahydrofuran, acetone, and mixtures thereof.    -   2.15. Dispersion 2.13, wherein the solvent or mixture of        solvents is selected from dioxane, methanol or a        dioxane/methanol mixture, e.g., a 90:10 to 98:2 ratio of dioxane        to methanol, or a 92:8 to 95:5 ratio, or about a 93:7 ratio of        dioxane to methanol.    -   2.16. Any foregoing dispersion, wherein the dispersion exhibits        any combination of characteristics as described in 2.1-2.15.

In a third embodiment, the present disclosure provides ITI-007 free basein the form of an amorphous solid dispersion comprising hydroxypropylmethyl cellulose phthalate (HPMC-P) excipient in a ratio of 25:75 to75:25 ITI-007 free base to HPMC-P (Dispersion 3). The present disclosurefurther provides the following Compositions:

-   -   3.1. Dispersion 3, wherein the dispersion comprises ITI-007 free        base and HPMC-P in a weight ratio of from 25:75 up to 75:25, but        excluding the ratios 25:75 and 75:25.    -   3.2. Dispersion 3 or 3.1, wherein the dispersion comprises        ITI-007 free base and HPMC-P in a weight ratio of 26:74 to        74:26, e.g., 30:70 to 70:30, or 35:65 to 65:35, or 40:60 to        60:40, or 42:58 to 58:42, or 44:56 to 56:44, or 45:55 to 55:45,        or 47:53 to 53:47, or 48:52 to 52:48, or 49:51 to 51:49, or        about 50:50.    -   3.3. Any foregoing dispersion, wherein the dispersion is x-ray        amorphous, e.g., as shown by XRPD analysis.    -   3.4. Any foregoing dispersion, wherein the X-ray diffraction        pattern is free of peaks characteristic of the excipient.    -   3.5. Any foregoing dispersion, wherein the dispersion shows a        single glass transition temperature (T_(g)) above 75° C., e.g.,        at a temperature above 80° C., or at a temperature above 85° C.,        e.g., as shown by mDSC analysis.    -   3.6. Dispersion 3.5, wherein the dispersion shows a single glass        transition temperature above 90° C., or between 92° C. and 98°        C., or at about 95° C.    -   3.7. Any foregoing dispersion, wherein the dispersion shows a        change in heat capacity (ΔCp) of 0.1 to 0.5 J/g-° C., e.g., from        0.2 to 0.4 J/g-° C., or about 0.3 J/g-° C., e.g., as shown by        mDSC.    -   3.8. Any foregoing dispersion, wherein the dispersion shows less        than 10% weight loss up to a temperature of 100° C., e.g., as        shown by TGA analysis.    -   3.9. Dispersion 3.8, wherein the dispersion shows less than 8%        weight loss up to a temperature of 100° C., e.g., less than 7%        weight loss, or less than 6% weight loss, or less than 5% weight        loss, or less than 4% weight loss, or less than 3% weight loss,        up to a temperature of 100° C.    -   3.10. Any foregoing dispersion, wherein the dispersion shows no        changes in appearance or texture after 7 days at 75% relative        humidity at 40° C.    -   3.11. Any foregoing dispersion, wherein the dispersion shows        greater than 90% chemical stability of ITI-007 after 7 days at        75% relative humidity at 40° C., e.g., as judged by HPLC.    -   3.12. Dispersion 3.11, wherein the dispersion shows greater than        95%, or greater than 96%, or greater than 97% or greater than        98%, or greater than 99% chemical stability of ITI-007 after 7        days at 75% relative humidity at 40° C.    -   3.13. Any foregoing dispersion, wherein the dispersion is        manufactured by a method comprising dissolving ITI-007 free base        and the selected excipient in a suitable solvent or mixture of        solvents and removing the solvent, e.g., by lyophilizing the        solution, to obtain the amorphous solid dispersion.    -   3.14. Dispersion 3.13, wherein the solvent or mixture of        solvents is selected from dioxane, methanol, ethanol,        tetrahydrofuran, acetone, and mixtures thereof.    -   3.15. Dispersion 3.13, wherein the solvent or mixture of        solvents is selected from dioxane, methanol or a        dioxane/methanol mixture, e.g., a 90:10 to 98:2 ratio of dioxane        to methanol, or a 92:8 to 95:5 ratio, or about a 93:7 ratio of        dioxane to methanol.    -   3.16. Any foregoing dispersion, wherein the dispersion exhibits        any combination of characteristics as described in 3.1-3.15.

In a fourth embodiment, the present disclosure provides ITI-007 tosylatesalt in the form of an amorphous solid dispersion comprising astabilizing excipient and optionally further comprising an anti-oxidantand/or a surfactant (Dispersion 4). For example, the stabilizingexcipient is an excipient which stabilizes the amorphous from of ITI-007tosylate to prevent conversion of the amorphous form to the crystalform. The present disclosure further provides the followingCompositions:

-   -   4.1. Dispersion 4, wherein the dispersion comprises ITI-007        tosylate salt and a stabilizing excipient selected from the        group consisting of cellulose acetate, cellulose acetate        phthalate, methacrylate/methyl acrylate copolymer, hydroxypropyl        cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl        cellulose acetate succinate (HPMC-AS), hydroxypropyl methyl        cellulose phthalate (HPMC-P), polyvinyl acetate, polyvinyl        pyrrolidone, polyvinyl pyrrolidone/vinyl acetate copolymer, and        polyethylene glycol/polyvinyl acetate/polyvinylcaprolactam        copolymer.    -   4.2. Dispersion 4 or 4.1, wherein the composition comprises        ITI-007 tosylate salt in admixture with a single stabilizing        excipient.    -   4.3. Dispersion 4 or 4.1, wherein the composition comprises        ITI-007 tosylate salt in admixture with two stabilizing        excipients.    -   4.4. Dispersion 4 or any of 4.1 to 4.3, wherein the dispersion        comprises ITI-007 tosylate salt in admixture with one or more        stabilizing excipients in a weight ratio of 25:75 to 75:25,        e.g., 26:74 to 74:26, or 30:70 to 70:30, or 35:65 to 65:35, or        40:60 to 60:40, or 42:58 to 58:42, or 44:56 to 56:44, or 45:55        to 55:45, or 47:53 to 53:47, or 48:52 to 52:48, or 49:51 to        51:49, or about 50:50.    -   4.5. Dispersion 4 or any of 4.1 to 4.3, wherein the dispersion        comprises ITI-007 tosylate salt in admixture with one or more        stabilizing excipients in a weight ratio of 5:95 to 50:50, e.g.,        5:95 to 49:51, or 5:95 to 45:55, or 10:90 to 40:60, or 15:85 to        35:65, or 20:80 to 30:70, or 22:78 to 28:82, or 23:77 to 27:83,        or 24:76 to 26:74, or about 25:75.    -   4.6. Dispersion 4 or any of 4.1 to 4.3, wherein the dispersion        comprises ITI-007 tosylate salt in admixture with one or more        stabilizing excipients in a weight ratio of 50:50 to 95:5, e.g.,        51:49 to 95:5, or 55:45 to 95:5, or 60:40 to 90:10, or 65:45 to        85:15, or 70:30 to 80:20 or about 75:25.    -   4.7. Any foregoing dispersion, wherein the stabilizing excipient        comprises one or more of cellulose acetate, cellulose acetate        phthalate, hydroxypropyl cellulose, hydroxypropyl methyl        cellulose, hydroxypropyl methyl cellulose acetate succinate        (HPMC-AS), and hydroxypropyl methyl cellulose phthalate        (HPMC-P).    -   4.8. Any foregoing dispersion, wherein the stabilizing excipient        comprises one or more of cellulose acetate, cellulose acetate        phthalate, and hydroxypropyl methyl cellulose phthalate.    -   4.9. Any foregoing dispersion, further comprising an        anti-oxidant.    -   4.10. Dispersion 4.9, wherein the anti-oxidant is selected from        one or more of tocopherol, butylated hydroxytoluene (BHT),        propyl gallate (OPG), and ascorbic acid.    -   4.11. Dispersion 4.9 or 4.10, wherein the dispersion comprises        the antioxidant in an amount of 0.1 to 10% by weight, e.g., 0.5        to 5% or 0.5 to 3% by weight of the dispersion.    -   4.12. Any foregoing dispersion, further comprising a surfactant,        for example, an anionic or cationic or neutral surfactants, such        as a surfactant which stabilizes the amorphous form ITI-007        tosylate (e.g., to prevent conversion to an ITI-007 tosylate        crystal form).    -   4.13. Any foregoing dispersion, wherein the dispersion is x-ray        amorphous, e.g., as shown by XRPD analysis.    -   4.14. Any foregoing dispersion, wherein the X-ray diffraction        pattern is free of peaks characteristic of the excipient(s).    -   4.15. Any foregoing dispersion, wherein the dispersion shows a        single glass transition temperature (T_(g)) above 75° C., e.g.,        at a temperature above 80° C., or at a temperature above 90° C.,        or a temperature about 100° C., or at a temperature above 110°        C., e.g., as shown by mDSC analysis.    -   4.16. Any foregoing dispersion, wherein the dispersion shows a        change in heat capacity (ΔCp) of 0.1 to 2.0 J/g-° C., e.g., from        0.1 to 1.5 J/g-° C., or 0.1 to 1.0 J/g-° C., or 0.1 to 0.5 J/g-°        C., e.g., as shown by mDSC.    -   4.17. Any foregoing dispersion, wherein the dispersion shows        less than 20% weight loss up to a temperature of 150° C., e.g.,        as shown by TGA analysis.    -   4.18. Dispersion 4.13, wherein the dispersion shows less than        15% weight loss up to a temperature of 150° C., e.g., less than        15% weight loss up to a temperature of 100° C., or less than 10%        weight loss up to a temperature of 150° C., or less than 10%        weight loss up to a temperature of 100° C., or less than 5%        weight loss up to a temperature of 150° C., or less than 5%        weight loss up to a temperature of 100° C.    -   4.19. Any foregoing dispersion, wherein the dispersion shows no        changes in appearance or texture after 7 days at 75% relative        humidity at 40° C.    -   4.20. Any foregoing dispersion, wherein the dispersion shows        greater than 85% chemical stability of ITI-007 after 7 days at        75% relative humidity at 40° C., e.g., as judged by HPLC.    -   4.21. Dispersion 4.20, wherein the dispersion shows greater than        90%, or greater than 95%, or greater than 96%, or greater than        97% or greater than 98%, or greater than 99% chemical stability        of ITI-007 after 7 days at 75% relative humidity at 40° C.    -   4.22. Any foregoing dispersion, wherein the dispersion is        manufactured by a method comprising dissolving ITI-007 tosylate        salt and the selected excipient(s) in a suitable solvent or        mixture of solvents and removing the solvent, e.g., by        lyophilizing the solution or evaporating the solvent (e.g., by        rotary evaporation), to obtain the amorphous solid dispersion.    -   4.23. Dispersion 4.22, wherein the solvent or mixture of        solvents is selected from dioxane, methanol, ethanol,        tetrahydrofuran, acetone, and mixtures thereof.    -   4.24. Dispersion 4.23, wherein the solvent or mixture of        solvents is selected from dioxane, methanol or a        dioxane/methanol mixture, e.g., a 90:10 to 98:2 ratio of dioxane        to methanol, or a 92:8 to 95:5 ratio, or about a 93:7 ratio of        dioxane to methanol.    -   4.25. Dispersion 4.22, 4.23, or 4.24, wherein the method further        comprises adding an anti-oxidant or a surfactant to the solvent        mixture prior to removing the solvent.    -   4.26. Any foregoing dispersion, wherein the dispersion exhibits        any combination of characteristics as described in 4.1-4.25.

Dispersion 4, and any of 4.1-4.26, may comprise an antioxidant toimprove the stability of the ITI-007 tosylate salt amorphous form. Insome embodiments, the anti-oxidant is selected from one or more oftocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), andascorbic acid.

In other embodiments the antioxidant may be selected from additionalsuitable antioxidants, such as butylated hydroxyanisole (BHA),tert-Butylhydroquinone (TBHQ), carotenoids, glutathione, sodiummetabisulfite, sodium ethylenediaminetetraacetate, cysteine, methionine,sesamol, and citric acid.

Dispersion 4, and any of 4.1-4.26, may comprise a surfactant to improvethe stability of the ITI-007 tosylate salt amorphous form. In someembodiments, the surfactant is a surfactant which stabilizes theamorphous form ITI-007 tosylate (e.g., to prevent conversion to anITI-007 tosylate crystal form). In some embodiments, the surfactant isselected from one or more of an anionic or cationic or neutralsurfactant.

In some embodiments of the present disclosure, Dispersion 4, or any of4.1-4.26, may further comprise any other excipient which can prevent orinhibit the formation of the crystal form of ITI-007 tosylate, or whichcan prevent or inhibit the conversion of the amorphous form of ITI-007tosylate to a crystal form of ITI-007 tosylate. Such excipients mayinclude polymers, gums, surfactants, wetting agents, drying agents, pHmodifiers, fillers, disintegrants, coatings, binders, or any othersuitable pharmaceutically acceptable excipients.

In a second aspect, the present disclosure provides a process(Process 1) for the production of Dispersion 1, et seq., or Dispersion2, et seq., or Dispersion 3, et seq., comprising the steps of:

-   -   (a) combining        1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one        (ITI-007) free base with the selected excipient in a suitable        solvent or mixture of solvents, e.g., selected from dioxane,        methanol, ethanol, tetrahydrofuran, acetone, and mixtures        thereof; and (b) removing the solvent and recovering the        amorphous solid dispersion thus formed, e.g., by lyophilization        of the solution.

In another embodiment of the second aspect, the present disclosureprovides a process (Process 2) for the production of Dispersion 4, etseq., comprising the steps of:

-   -   (a) combining        1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one        (ITI-007) tosylate salt, e.g., monotosylate, optionally in        crystal form, with the selected excipient or excipients in a        suitable solvent or mixture of solvents, e.g., selected from        dioxane, methanol, ethanol, tetrahydrofuran, acetone, and        mixtures thereof; and    -   (b) removing the solvent and recovering the amorphous solid        dispersion thus formed, e.g., by lyophilization of the solution        or evaporating the solvent (e.g., by rotary evaporation).

In some embodiments, Process 2 further comprises the step of adding oneor more anti-oxidants and/or one or more surfactants to the solvent ormixture of solvents in step (a). In some embodiments, the anti-oxidantis selected from one or more of tocopherol, butylated hydroxytoluene(BHT), propyl gallate (OPG), and ascorbic acid. In some embodiments, theone or more surfactants may comprise an anionic or cationic or neutralsurfactant. For example, the surfactant may be a surfactant whichstabilizes the amorphous form ITI-007 tosylate, such as to preventconversion of the amorphous form to an ITI-007 tosylate crystal form).

In other embodiments, the antioxidant may be selected from additionalsuitable antioxidants, such as butylated hydroxyanisole (BHA),tert-Butylhydroquinone (TBHQ), carotenoids, glutathione, sodiummetabisulfite, sodium ethylenediaminetetraacetate, cysteine, methionine,sesamol, and citric acid.

In another embodiment of the second aspect, the solvent or mixture ofsolvents for Process 1 is selected from dioxane, methanol or adioxane/methanol mixture, e.g., a 90:10 to 98:2 ratio of dioxane tomethanol, or a 92:8 to 95:5 ratio, or about a 93:7 ratio of dioxane tomethanol, optionally wherein the solvent is removed by lyophilization.

Solid dispersion, as used herein, refers to the dispersion of an activepharmaceutical ingredient, i.e., ITI-007, in an inert excipient ormatrix (carrier), where the active ingredient could exist in a finelycrystalline, solubilized or amorphous state. The excipient in a soliddispersion is typically a polymer. The most important role of thepolymer in a solid dispersion is to reduce the molecular mobility of thepharmaceutical active to avoid phase separation and re-crystallizationof the active during storage. The amorphous form of the active isassociated with a higher energy state as compared to its crystallinecounterpart, and therefore, significantly less external energy isrequired to effect dissolution (e.g., in the gastrointestinal tract orelsewhere in the body).

In a third aspect, the present disclosure provides a pharmaceuticalcomposition (Composition 1) comprising Dispersion 1, et seq., orDispersion 2, et seq., or Dispersion 3, et seq., or Dispersion 4, etseq., in combination or association with a pharmaceutically acceptablediluent or carrier. In some embodiments, the pharmaceutical compositionis in the form of a tablet or capsule for oral administration. In someembodiments, the pharmaceutical composition is in the form of a depotformulation for use as a long-acting injectable (LAI). Thepharmaceutical composition may further comprise any suitablepharmaceutically acceptable excipient, such as: diluents such asstarches, pregelatinized starches, lactose, powdered celluloses,microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate,mannitol, sorbitol, xylitol, sugar and the like; binders such as acacia,guar gum, tragacanth, gelatin, polyvinylpyrrolidones such aspolyvinylpyrrolidones(PVP K-30, K-90), poly (vinyl pyrrolidone-co-vinylacetate) (PVP-VA) and the like, hydroxypropyl celluloses, hydroxypropylmethylcellulose, cellulose acetate, hydroxypropyl methylcelluloseacetate succinate (HPMC-AS) and the like; disintegrants such asstarches, sodium starch glycolate, pregelatinized starches,crospovidones, croscarmellose sodium and the like; lubricants such asstearic acid, magnesium stearate, zinc stearate and the like; glidantssuch as colloidal silicon dioxide and the like; solubility or wettingenhancers such as anionic or cationic or neutral surfactants;maltodextrin, complex forming agents such as various grades ofcyclodextrins and resins; release rate controlling agents such ashydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropylmethylcelluloses, ethylcelluloses, methylcelluloses, various grades ofmethyl methacrylates, waxes and the like; and film formers,plasticizers, colorants, flavoring agents, sweeteners, viscosityenhancers, preservatives, antioxidants, and the like.

In another embodiment of the third aspect, the composition may furthercomprise one or more anti-oxidants, for example, tocopherol, butylatedhydroxytoluene (BHT), propyl gallate (OPG), and ascorbic acid, or thelike. The inclusion of an anti-oxidant may further improve the chemicalstability of the dispersions by preventing oxidative chemicaldegradation of the ITI-007 active. In another embodiment, the dispersionitself is formulated to include such an anti-oxidant.

In another embodiment of the third aspect, the composition may furthercomprise any excipient which can prevent or inhibit the formation of thecrystal form of ITI-007 free base or ITI-007 tosylate, or which canprevent or inhibit the conversion of the amorphous form of ITI-007 freebase or ITI-007 tosylate to a crystal form thereof. Such excipients mayinclude polymers, gums, surfactants, wetting agents, drying agents, pHmodifiers, fillers, disintegrants, coatings, binders, or any othersuitable pharmaceutically acceptable excipients. Such excipients includeany one or more of the excipients described in paragraph [0033] above.

In another aspect, the present disclosure provides Dispersion 1, etseq., or Dispersion 2, et seq., or Dispersion 3, et seq., or Dispersion4, et seq., or a pharmaceutical composition comprising Dispersion 1, etseq., or Dispersion 2, et seq., or Dispersion 3, et seq., or Dispersion4, et seq., e.g., Composition 1, for use in treating a disease orabnormal condition involving or mediated by the 5-HT_(2A) receptor,serotonin transporter (SERT), and/or dopamine D₁/D₂ receptor signalingpathways, e.g., a disorder selected from obesity, anorexia, bulimia,depression, anxiety, psychosis, schizophrenia, migraine,obsessive-compulsive disorder, sexual disorders, depression,schizophrenia, migraine, attention deficit disorder, attention deficithyperactivity disorder, obsessive-compulsive disorder, sleep disorders,conditions associated with cephalic pain, social phobias, or dementia.

In another embodiment, the invention provides a method for theprophylaxis or treatment of a human suffering from a disease or abnormalcondition involving or mediated by the 5-HT_(2A) receptor, serotonintransporter (SERT), and/or dopamine D₁/D₂ receptor signaling pathways,e.g., a disorder selected from obesity, anorexia, bulimia, depression,anxiety, psychosis, schizophrenia, migraine, obsessive-compulsivedisorder, sexual disorders, depression, schizophrenia, migraine,attention deficit disorder, attention deficit hyperactivity disorder,obsessive-compulsive disorder, sleep disorders, conditions associatedwith cephalic pain, social phobias, or dementia, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of Dispersion 1, et seq., or Dispersion 2, et seq., or Dispersion3, et seq., or a pharmaceutical composition comprising Dispersion 1, etseq., or Dispersion 2, et seq., or Dispersion 3, et seq, or Dispersion4, et seq., e.g., Composition 1.

EXAMPLES

The following equipment and methods are used to isolate and characterizethe exemplified co-crystal forms:

X-ray powder diffraction (XRPD): The X-ray powder diffraction studiesare performed using a PANalytical X′Pert PRO MPD diffractometer using anincident beam of Cu radiation produced using an Optix long, fine-focussource. An elliptically graded multilayer mirror is used to focus Cu KαX-ray radiation through the specimen and onto the detector. Prior toanalysis, a silicon specimen is analyzed to verify the observed positionof the Si (111) peak (consistent with the NIST-certified position, NISTSM 640e). A specimen of the sample is sandwiched between 3-micron thickfilms and analyzed in transmission geometry. A beam-stop, shortantiscatter extension, and antiscatter knife edge is used to minimizethe background generated by the air. Soller slits for the incident anddiffracted beams are used to minimize broadening from axial divergence.Diffraction patterns are collected using a scanning position-sensitivedetector (X′Celerator) located 240 mm from the specimen. Data Collectorsoftware v. 2.2b is used for analysis.

Thermogravimetry (TGA) analysis: TGA is performed using a TA InstrumentsQ5000 or Discovery thermogravimetric analyzer. The sample is placed inan aluminum sample pan and is inserted into the TG furnace. Samples areheated from ambient temperature to 250° C. at a rate of 10° C./minute.Nickel and Alumel are used as the calibration standards.

Modulated Differential Scanning Calorimetry (mDSC): mDSC data isobtained on a TA Instruments Q2000 or 2920 differential scanningcalorimeter equipped with a refrigerated cooling system. Temperaturecalibration is performed using NIST traceable indium metal. The sampleis placed into an aluminum T-zero DSC pan, covered with a lid, and theweight is accurately recorded. A weighed aluminum pan configured as thesample pan is placed on the reference side of the cell. Typically, thestart temperature is −50° C. and the end temperature is 250° C., with amodulation amplitude of ±1° C. and a 50 second period with an underlyingheating rate of 2° C. per minute.

High performance liquid chromatography (HPLC): The high-performanceliquid chromatography analyses are performed using an Agilent 1100series liquid chromatograph equipped with a diode array detector,degasser, quaternary pump, and an auto sampler. The column is a 4.6×100mm CSH C18 column with 2.5-micron packing (XSelect) running with a 0.1%TFA in water mobile phase A and a 0.1% TFA in acetonitrile mobile phaseB, at a flow rate of 0.500 mL/minute. The gradient runs from 95% A to73% over the first 22 minutes, followed by 6 minutes at 73% A, andfollowed by 73% A to 30% A over the next 22 minutes. The columntemperature is set to 15.0° C., and the detector wavelength is 254 nmwith a bandwidth of 100 nm and a reference wavelength of 360 nm. Theinjection volume is 2.0 microliters.

Example 1: Preparation of Free Base Dispersions Solubility of ITI-007free base and various excipients is first evaluated in various solvents.It is found that ITI-007 free base shows good solubility (>50 mg/mL) inacetone, ethanol, methanol, dioxane, and 2,2,2-trifluoroethanol (TFE),but relatively poor solubility (5-50 mg/mL) in tert-butanol/watermixtures. However, it is found that solutions of ITI-007 free base inTFE rapidly discolor due to decomposition of the active.

The excipients evaluated are Eudragit L100, polyvinyl acetate,polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone K-90,polyvinylpyrrolidone S-630, cellulose acetate, cellulose acetatephthalate, Gelucire 50/13, glyceryl monostearate, hydroxypropylcellulose, hydroxypropyl methyl cellulose phthalate (HPMC-P),hydroxypropyl methyl acetate succinate (HPMC-AS), polyethylene glycol(PEG), PEG-100 succinate, Pluronic F-127, and Soluplus. Excipients wereevaluated at one or more of the ratios 25:75, 50:50 and 75:25 ITI-007free base to excipient.

Based on the solubility analyses, solutions of various excipients withITI-007 free base are prepared in 3:1 acetone-ethanol. Rotaryevaporation is attempted to remove the solvent, but this results in oilymaterials, instead of solids, in all cases.

Solid dispersions are successfully prepared by lyophilization fromsolutions of ITI-007 free base and excipient in either dioxane ordioxane-methanol (90:10, 91:9, 92:8, 93:7 or 94:6). Solutions areinitially frozen in a dry ice/acetone bath, and then placed in a freezedryer with the shelf pre-cooled to −75° C. Samples are dried overnightat −50° C., followed by −20° C., then 0° C. over a period of two days.Samples are then secondary dried at 20° C. for four hours, purged withnitrogen then stored in a freezer over desiccant until testing.

Example 2: Preliminary Screen of Free Base Dispersions

Solid dispersions obtained from Example 1 are first evaluated by XRPD todetermine if they are amorphous. All lyophilization samples usingamorphous excipients are found to be x-ray amorphous by XRPD.Lyophilization samples using crystalline excipients (Gelucire 50/13,PEG, PEG-1000 succinate, Pluronic F-127) are found to be disordered withpeaks present corresponding only to the excipient. Further observationsof the appearance of the solids are shown in Table 1 below. The 50:50ITI-007/PEG-1000 succinate dispersion is found to be very sticky and isnot further evaluated.

Example 3: Stability Evaluation of Free Base Dispersions

Solid dispersions from Example 1 are placed into uncapped clear glassvials and the vials are placed into a container maintained for sevendays at 75% relative humidity and a temperature of 40° C. As a control,a sample of ITI-007 free base is analyzed in parallel. Samples wereobserved visually as well as by polarized light microscopy (0.8-10×magnification with crossed polarizers and a first order redcompensator). Observations are shown in Table 1. The majority of samplesdisplay changes in appearance or texture, indicating the formation ofphysically unstable amorphous dispersions. For example, some showvisible crystallization while others become sticky solids or oils.

Dispersions which are physically stable free-flowing solids are furtheranalyzed by XRPD to confirm that they remain x-ray amorphous ordisordered with excipient peaks only. The XRPD results confirm that thevisually stable samples remain X-ray amorphous dispersions.

mDSC and TGA analysis is conducted on the physically stable free-flowingsamples. A single glass transition temperature in mDSC supports theconclusion that the solid is a non-crystalline miscible dispersion. Thetwo PEG dispersions show an unacceptable low-temperature glasstransition at 9 or 10° C., while the glyceryl monostearate dispersionshows no glass transition. The 50:50 cellulose acetate dispersion showstwo glass transition temperatures, which suggests a phase-separatedmaterial, which is unacceptable. Only the 25:75 cellulose acetate, 25:75cellulose acetate phthalate, 50:50 cellulose acetate phthalate, 25:75HPMC-AS, 50:50 HPMC-AS, 25:75 HPMC-P and 50:50 HPMC-P dispersions showacceptable single glass transition temperatures above 75° C.

All samples submitted to mDSC and TGA are then submitted to HPLCanalysis to determine the chemical stability of the ITI-007 active agentduring the seven-day study. As a control, the ITI-007 free base sampleis also analyzed by HPLC. All results are normalized to the ITI-007content shown by HPLC prior to the seven-day study. A loss of less than5% ITI-007 by HPLC is considered satisfactory.

Both HPMC-AS dispersions, as well as the 25:75 HPMC-P dispersion showvery high material losses by HPLC. The 25:75 cellulose acetate phthalatedispersion shows a low but unacceptable loss of material. Only sevendispersions produce satisfactory results: 25:75 cellulose acetate, 50:50cellulose acetate, 50:50 cellulose acetate phthalate, 50:50 HPMC-P,25:75 PEG, 50:50 PEG and 25:75 glyceryl stearate. These dispersions arethus chemically stable.

The combined tests results are shown in Table 1 below.

ITI- X-ray Stable for 7 % ITI-007 007/Excipient Amorphous days at 40change by Excipient Ratio Solids? ° C./75% RH T_(g) > 75° C. HPLCCellulose 25:75 Yes Yes Yes (167° C.) 0% Acetate 50:50 Yes Yes No −4.43% 75:25 Yes No Cellulose 25:75 Yes Yes Yes (142° C.)  −5.65%Acetate 50:50 Yes Yes Yes (107° C.)  −2.42% Phthalate 75:25 Yes NoGelucire 25:75 No No 50/13 50:50 No No Glyceryl 25:75 No No No  0%Monostearate 50:50 No No HPC 25:75 Yes No 50:50 Yes No HPMC-AS 25:75 YesYes (88° C.) −55.29% MG 50:50 Yes Yes (77° C.)  −8.76% 75:25 Yes NoHPMC-P 25:75 Yes Yes (123° C.) −18.89% 50:50 Yes Yes (95° C.)  0.01%75:25 Yes No PEG 25:75 No No No  −0.30% 50:50 No No No  0% 75:25 No NoPEG-1000 25:75 No No Succinate 50:50 No Pluronic F- 25:75 No No 12750:50 No No PVAc 25:75 Yes No 50:50 Yes No PVP S-630 25:75 Yes No 50:50Yes No 75:25 Yes No PVP K-90 25:75 Yes No 50:50 Yes No 75:25 Yes No PVPco-VA 25:75 Yes No 50:50 Yes No 75:25 Yes No Soluplus 25:75 Yes No 50:50Yes No 75:25 Yes No ITI-007 only 100:0 No No  −5.97%

Of the tested dispersions, it is found that only three are bothchemically stable and physically stable: 25:75 cellulose acetate, 50:50cellulose acetate phthalate, and 50:50 HPMC-P.

It is noted that similar experiments conducted using ITI-007 tosylatesalt, instead of ITI-007 free base, result in no completely stableamorphous dispersions. These results are shown in more detail in Example4 below. While most of the ITI-007 tosylate dispersions pass the initialscreen (X-ray amorphous or showing only X-ray peaks due to theexcipient), all of the resulting initial dispersions display strongphysical instability (color and appearance changes, includingcrystallization of the active agent out of the dispersion) or chemicalinstability (10-68% decomposition by HPLC). For example, the 25:75dispersion of ITI-007 tosylate with cellulose acetate producedcrystallization of ITI-007 during the aging study; the 50:50 dispersionof ITI-007 tosylate with cellulose acetate phthalate showed about a 52%decrease in ITI-007 content by HPLC; and the 50:50 dispersion of ITI-007tosylate with HPMC-P showed about a 68% decrease in ITI-007 content byHPLC. These results are unexpected because ITI-007 tosylate ischemically more stable than ITI-007 free base. Thus, it is particularlyunexpected that three specific amorphous solid dispersions of ITI-007free base are physically and chemically stable whereas the correspondingdispersions of ITI-007 tosylate are not.

Example 4: Preparation, Preliminary Screen and Stability Evaluation ofTosylate Dispersions

The procedures described in Example 1, 2 and 3 are repeated usingITI-007 tosylate salt as the active ingredient. It is found that ITI-007tosylate has good solubility (>50 mg/mL) in 2,2,2-trifluoroethanol (TFE)and in a 60:40 v/v mixture of tert-butanol/water, but relatively poorsolubility (20-40 mg/mL) in acetone, ethanol, dioxane and othertert-butanol/water mixtures. However, it is also found that solutions ofITI-007 tosylate salt in TFE rapidly discolor due to decomposition ofthe active.

The same excipients are evaluated as described in Example 1. As is seenfor the free base, rotary evaporation from solvent (3:1acetone-methanol) does not result in amorphous material, butlyophilization from dioxane and dioxane/methanol mixtures results inamorphous material using each excipient tested. Screening and stabilityevaluations are shown in Table 2 below.

ITI- X-ray Stable for 7 % ITI-007 007/Excipient Amorphous days at 40change by Excipient Ratio Solids? ° C./75% RH T_(g) > 75° C. HPLCCellulose 25:75 Yes Some Crystal Acetate 50:50 Yes Some CrystalCellulose 25:75 Yes Color change Yes (131° C.) −23.30% Acetate 50:50 YesColor change Yes (112° C.) −52.14% Phthalate 75:25 Yes Texture changeGelucire 25:75 No Some Crystal 50/13 50:50 No Some Crystal Glyceryl25:75 No Some Crystal Monostearate 50:50 No Some Crystal HPC 25:75 YesTexture change 50:50 Yes Texture change 75:25 Yes Texture changeHPMC-ASMG 25:75 Yes Color change Yes (91° C.) −12.10% 50:50 Yes Texturechange 75:25 Yes Texture change HPMC-P 25:75 Yes Color change Yes (116°C.) −23.11% 50:50 Yes Color change Yes (94° C.) −67.77% 75:25 YesTexture change PEG 25:75 No Some Crystal 50:50 No Some Crystal PEG-100025:75 No Texture change Succinate 50:50 No Texture change Pluronic F-25:75 No Texture change 127 50:50 No Some Crystal PVAc 25:75 Yes Texturechange 50:50 Yes Texture change PVP S-630 25:75 Yes Texture change 50:50Yes Texture change 75:25 Yes Texture change PVP K-90 25:75 Yes Texturechange 50:50 Yes Texture change 75:25 Yes Texture change PVP co-VA 25:75Yes Texture change 50:50 Yes Texture change Soluplus 25:75 Yes Texturechange 50:50 Yes Texture change 75:25 Yes Texture change ITI-007 only100:0 Yes Some crystal No  0.00%

Of the tested dispersions using ITI-007 tosylate salt, most of are foundto be amorphous and under the harsh storage conditions of 75% relativehumidity and a temperature of 40° C., several dispersions are observedvisually to have undergone some crystallization. In addition, otherdispersions are found to have undergone some minor color changes ortexture changes. Further evaluation suggests, however, that thesechanges in physical appearance may be prevented by incorporating ananti-oxidant into the composition to prevent air-promoted oxidation,forming the dispersion into a coated tablet, encapsulating thedispersion into a gel caplet or capsule, adding excipient(s), such aspolymers, to prevent partial conversion of amorphous formulation tocrystallized forms, and/or admixing the dispersion with surfactant toinhibit particle agglomeration.

What is claimed:
 1. (canceled)
 2. A method for the treatment of a humansuffering from a disease or disorder selected from the group consistingof obesity, anorexia, bulimia, depression, anxiety, psychosis,schizophrenia, migraine, obsessive-compulsive disorder, sexualdisorders, depression, schizophrenia, migraine, attention deficitdisorder, attention deficit hyperactivity disorder, obsessive-compulsivedisorder, sleep disorders, conditions associated with cephalic pain,social phobias, or dementia, comprising administering to a patient inneed thereof a therapeutically effective amount of an amorphous soliddispersion comprising1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(ITI-007) tosylate salt and a stabilizing excipient and optionallyfurther comprising an anti-oxidant and/or a surfactant, wherein thestabilizing excipient is selected from the group consisting of celluloseacetate phthalate, hydroxypropyl methyl cellulose acetate succinate,hydroxypropyl methyl cellulose phthalate, cellulose acetate,hydroxypropyl cellulose, polyvinyl acetate, polyvinyl pyrrolidone,polyvinyl pyrrolidone/vinyl acetate copolymer, and polyethyleneglycol/polyvinyl acetate/polyvinylcaprolactam copolymer.
 3. The methodof claim 2, wherein the dispersion comprises ITI-007 tosylate salt and astabilizing excipient selected from the group consisting of, celluloseacetate phthalate, hydroxypropyl methyl cellulose acetate succinate, andhydroxypropyl methyl cellulose phthalate.
 4. The method of claim 2,wherein the dispersion further comprises an anti-oxidant, optionallyselected from one or more of tocopherol, butylated hydroxytoluene (BHT),propyl gallate (OPG), and ascorbic acid.
 5. The method of claim 2,wherein the dispersion further comprises a surfactant, optionally ananionic or cationic or neutral surfactant.
 6. The method of claim 2,wherein the dispersion is x-ray amorphous.
 7. The method according toclaim 2, wherein the amorphous solid dispersion is administered as apharmaceutical composition comprising the dispersion 2, in combinationor association with a pharmaceutically acceptable diluent or carrier. 8.The method of claim 7, wherein the composition is in the form of atablet or capsule for oral administration.
 9. The method of claim 2,wherein the disease or disorder is selected from obesity, anorexia,bulimia, depression, anxiety, psychosis, schizophrenia, migraine,obsessive-compulsive disorder, sexual disorders, depression,schizophrenia, migraine, attention deficit disorder, attention deficithyperactivity disorder, obsessive-compulsive disorder, sleep disorders,conditions associated with cephalic pain, social phobias, or dementia.10. A process for the production of the dispersion described in claim 2comprising the steps of: (a) combining1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(ITI-007) tosylate salt optionally in crystal form, with the selectedexcipient or excipients in a suitable solvent or mixture of solvents;and (b) removing the solvent and recovering the amorphous soliddispersion thus formed.
 11. The dispersion method of claim 12, whereinthe dispersion is1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(ITI-007) free base and: (a) cellulose acetate excipient in a ratio of5:95 to 50:50 ITI-007 free base to cellulose acetate; or (b) celluloseacetate phthalate excipient in a ratio of 25:75 to 75:25 ITI-007 freebase to cellulose acetate phthalate; or (c) HPMC-P excipient in a ratioof 25:75 to 75:25 ITI-007 free base to HPMC-P.
 12. The method of claim11, wherein the dispersion comprises cellulose acetate excipient in aratio of 5:95 to 50:50 ITI-007 free base to cellulose acetate.
 13. Themethod of claim 12, wherein the dispersion comprises ITI-007 free baseand cellulose acetate in a weight ratio of 5:95 up to 50:50, butexcluding the ratio 50:50.
 14. The method of claim 11, wherein thedispersion comprises cellulose acetate phthalate excipient in a ratio of25:75 to 75:25 ITI-007 free base to cellulose acetate phthalate.
 15. Themethod of claim 14, wherein the dispersion comprises ITI-007 free baseand cellulose acetate phthalate in a weight ratio of from 25:75 up to75:25, but excluding the ratios 25:75 and 75:25.
 16. The method of claim11, wherein the dispersion comprises HPMC-P excipient in a ratio of25:75 to 75:25 ITI-007 free base to HPMC-P.
 17. The method of claim 16,wherein the dispersion comprises ITI-007 free base and HPMC-P in aweight ratio of from 25:75 up to 75:25, but excluding the ratios 25:75and 75:25.
 18. The method of claim 11, wherein the dispersion is x-rayamorphous.
 19. The method of claim 2, wherein the dispersion has anX-ray diffraction pattern which is free of peaks characteristic of theexcipient.
 20. The method of claim 2, wherein the dispersion ismanufactured by a method comprising dissolving ITI-007 free base and theselected excipient in a suitable solvent or mixture of solvents andremoving the solvent to obtain the amorphous solid dispersion. 21.(canceled)
 22. (canceled)
 23. (canceled)
 24. (canceled)
 25. (canceled)26. (canceled)
 27. The method of claim 7, wherein the composition is inthe form of a depot formulation for use as a long-acting injectable(LAI).
 28. (canceled)
 29. The method of claim 2, wherein the thestabilizing excipient is selected from the group consisting of: (a)cellulose acetate phthalate, at a weight ratio of 10:90 to 40:60 or35:65 to 65:35 of ITI-007 to cellulose acetate phthalate; or (b)hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), at a weightratio of 10:90 to 40:60 of ITI-007 to HPMC-AS; or (c) hydroxypropylmethyl cellulose phthalate (HPMC-P), at a weight ratio of 10:90 to 40:60or 35:65 to 65:35 of ITI-007 to HPMC-P.
 30. The method of claim 2,wherein the stabilizing excipient is selected from the group consistingof: (a) cellulose acetate phthalate, at a weight ratio of 20:80 to 30:70or 40:60 to 60:40 of ITI-007 to cellulose acetate phthalate; or (b)hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), at a weightratio of 20:80 to 30:70 of ITI-007 to HPMC-AS; or (c) hydroxypropylmethyl cellulose phthalate (HPMC-P), at a weight ratio of 20:80 to 30:70or 40:60 to 60:40 of ITI-007 to HPMC-P
 31. The method of claim 2,wherein the stabilizing excipient is cellulose acetate phthalate, andwherein the dispersion comprises ITI-007 tosylate salt in admixture withthe stabilizing excipient in a weight ratio of 25:75 or 50:50.
 32. Themethod of claim 2, wherein the stabilizing excipient is hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), and wherein the dispersioncomprises ITI-007 tosylate salt in admixture with the stabilizingexcipient in a weight ratio of 25:75.
 33. The method of claim 2, whereinthe stabilizing excipient is hydroxypropyl methyl cellulose phthalate(HPMC-P), and wherein the dispersion comprises ITI-007 tosylate salt inadmixture with the stabilizing excipients in a weight ratio of 25:75 or50:50.